The invention concerns water-soluble compositions comprising folic acid and/or folic acid analogs, and at least one carbonate or bicarbonate material, methods for making such compositions, and methods for making pharmaceutical dosage forms thereof.
Folic acid has the empirical formula C.sub.19 H.sub.19 N.sub.7 O.sub.6 and the structural formula shown below. It is a B vitamin that is found in liver, kidney, mushrooms, spinach, yeast, green leaves, and grasses. Pure folic acid crystals are yellowish-orange and only very slightly soluble in cold water (0.0016 mg/ml at 25.degree. C.). ##STR1##
Absorption of folic acid by the body is facilitated by enzymes associated with the mucosal cell membrane. More specifically, absorption primarily occurs in the mucosae of the upper intestine, known as the jejunum and duodenum. Insufficient folic acid in the diet and the inability to absorb folic acid can cause anemia and/or birth defects, namely, anecephaly and spina bifida, the latter resulting in brain development abnormalities and even death.
Anecephaly and spina bifida are caused by neural tube defects and the frequency of these defects can be greatly decreased by supplementing the diets of pregnant women with folic acid. The discovery of the importance of folic acid stemmed from a finding that women from lower socioeconomic backgrounds gave birth to infants with neural tube defects at a higher rate than women who were well off and presumably had a well-rounded diet. Researches also found that babies that were conceived during the fall and winter were at an increased risk of neural tube defects, presumably because of the lack of fresh vegetables during the pregnancy. This information lead to the U.S. Public Health Service recommendation in September 1992 that all women of childbearing age consume 400 .mu.g of folic acid daily.
In February 1996, the Food and Drug Administration recommended that certain foods that are regularly consumed by the public be fortified with folic acid. This action was taken as a preventative measure since most neural tube defects occur in the first 18-30 days of pregnancy, when most women are unaware of the pregnancy.
More recently, epidemiological studies have implicated folic acid in atherosclerosis. Researchers have found elevated levels of homocysteine, an amino acid in the blood, in people suffering from atherosclerosis. Folic acid and other B vitamins contribute to the breakdown of homocysteine and therefore may be useful for controlling atherosclerosis.
While much is known about the benefits derived from folic acid, its very low aqueous solubility have made it difficult to use and administer. Recent studies indicate that dietary supplements containing folic acid generally have failed to meet the United States Pharmacopeia (USP) Convention for dissolution, which is that 75% of the folic acid content in the supplement dissolve in an aqueous medium within one hour, the time regarded to be necessary for folic acid to pass through the stomach and into the intestine where absorption occurs. See 37 J. Am. Pharm. Assoc. 397 (1997) Therefore, compositions and methods for increasing the aqueous solubility of folic acid are needed so that folic acid utilization can be optimized.